Developing New 4‑PIOL and 4‑PHP Analogues for Photoinactivation of γ‑Aminobutyric Acid Type A Receptors

The critical roles played by GABA_A receptors as inhibitory regulators of excitation in the central nervous system has been known for many years. Aberrant GABA_A receptor function and trafficking deficits have also been associated with several diseases including anxiety, depression, epilepsy, and insomnia. As a consequence, important drug groups such as the benzodiazepines, barbiturates, and many general anesthetics have become established as modulators of GABA_A receptor activity. Nevertheless, there is much we do not understand about the roles and mechanisms of GABA_A receptors at neural network and systems levels. It is therefore crucial to develop novel technologies and especially chemical entities that can interrogate GABA_A receptor function in the nervous system. Here, we describe the chemistry and characterization of a novel set of 4-PIOL and 4-PHP analogues synthesized with the aim of developing a toolkit of drugs that can photoinactivate GABA_A receptors. Most of these new analogues show higher affinities/potencies compared with the respective lead compounds. This is indicative of cavernous areas being present near their binding sites that can be potentially associated with novel receptor interactions. The 4-PHP azide-analogue, 2d, possesses particularly impressive nanomolar affinity/potency and is an effective UV-inducible photoinhibitor of GABA_A receptors with considerable potential for photocontrol of GABA_A receptor function in situ.